Recent findings from genomewide association studies in AS and other spondyloarthritis (SpA)-related diseases, such as inflammatory bowel disease (IBD) and psoriasis suggest networks of shared and disease specific genes in pathogenesis. In the past few years, axial SpA has emerged as a discrete entity for which specific criteria have been developed This proposal is aimed at further evaluation the spectrum of SpA in first degree relatives (FDRs) of AS patients, particularly of new onset axial SpA, and to assess co-morbidities that could explain the diminishing frequency of HLA-B27 with age. Having developed an instrument through the U.S. National Health and Nutrition Examination Survey (NHANES), and validated it in over 137 FDRs of AS patients for inflammatory low back pain (IBP) and axial SpA, which will be further examined in additional FDRs with the range of other SpA manifestations in order to have a better statistical power for calculation of accuracy of each component (Aim 1). We will administer the instrument to all FDR's of AS patients participating in Project 2 either by mail or by clinical/ serologic evaluation in the Clinical Research Units (CPU's) and serum CRP will be assessed to assess chronic inflammation (from those evaluated in person) or DNA obtained from saliva samples (from those examined by mail) (Aim 2). Genetic analysis of genes known to be associated with AS susceptibility (HLA-B27, ERAPl, IL23R, gene deserts at chromosome 2p15 and 21q22, etc will be carried out comparing affected versus unaffected FDR's (an unaffected FDR defined at having reached the age of 40 years without any signs/symptoms of SpA on questionaire evaluation) with the intent of finding potential biomarkers of disease susceptibility in the FDRs. Based on data from the 2009 NHANES study showing a significantly diminished frequency of HLA-B27 in individuals over the age of 50 years, we will carry out a cross-sectional evaluation in FDRs, by questionnaire or clinical evaluation, for comorbidities potentially associated with SpA, particularly cardiovascular disease (Aim 3) and also hyperiipidemia/ hypercholesterolemia, hypertension, diabetes mellitus, and malignancy.